PROJECT SUMMARY/ABSTRACT There is substantial evidence from epidemiologic studies indicating that early life factors play an important role in the etiology of adult cancers. In particular, body size in early life - including birth weight and adiposity during childhood and adolescence - consistently has been associated with risk of several common cancers in adulthood. Currently, the underlying mechanisms behind these associations are not understood;however, the insulin-like growth factor (IGF) axis, which has been implicated in cancer development and progression, represents a biologic pathway that could provide a unifying explanation. In this application, we propose to evaluate whether birth weight and adiposity during childhood and adolescence have long-term influences on circulating levels of IGF-I and IGFBP-3 in adulthood, and whether common variation in the IGF-I and IGFBP-3 genes is related to these measures of body size in early life. We will utilize previously collected questionnaire data, blood, and cheek cell samples from over 4200 participants in the Nurses'Health Study (NHS). Plasma levels of IGF-I and IGFBP-3 and IGF genotype data for these women are already available. We will assess the cross-sectional relations of IGF-I and IGFBP-3 levels with birth weight, body shape at ages 5 and 10, and body mass index at age 18. In addition, we will examine associations of IGF polymorphisms and haplotypes with body size in early life. The NHS represents a unique resource for addressing these questions, given that it brings together high-quality data on early life factors, circulating IGF concentrations, IGF genotype, and other potential confounding factors for a large number of women. This will be the largest and most comprehensive study of body size in early life and the IGF pathway to date. The proposed study will help to elucidate the biologic mechanisms underlying associations observed in epidemiologic studies, including our own, between body size in early life and risk of cancer in adulthood. Clarifying these mechanisms is important from a public health standpoint to identify and develop effective strategies for cancer prevention, particularly since body size is a modifiable risk factor. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Birth weight and adiposity during childhood and adolescence have been associated with risk of several common cancers in adulthood, and the insulin-like growth factor (IGF) axis represents a potential biologic pathway. This application aims to evaluate whether birth weight and adiposity during childhood and adolescence have long-term influences on circulating IGF levels in adulthood and whether genetic variation in IGF is related to these body size measures, using data from the Nurses'Health Study. Clarifying the mechanisms that explain the associations of early life factors with adult cancer risk is important to identify effective prevention strategies, particularly since body size is a modifiable risk factor.